CN107496936B - Amphiphilic small molecule self-assembly targeting nanoparticle drug delivery system and preparation method thereof - Google Patents
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Abstract
The invention discloses an amphiphilic small-molecule self-assembly targeting nanoparticle drug delivery system, which comprises 2-glucosamine-fluorescent dye FITC and paclitaxel, wherein the 2-glucosamine-fluorescent dye FITC is used as a hydrophilic end of a small molecule, the paclitaxel is used as a hydrophobic end of the small molecule, and the targeting nanoparticle drug delivery system is self-assembled by a nano-precipitation method. The invention also discloses a preparation method of the amphiphilic micromolecule self-assembly targeting nanoparticle drug delivery system, wherein the targeting amphiphilic micromolecule 2DA-FITC-PTX is synthesized firstly, the targeting 2DA-FITC-PTXNP drug delivery system is prepared by adopting a nano precipitation method, the particle size of the drug delivery system is 42 +/-4 nm, the particle size is uniform, the drug delivery efficiency is up to 98 percent, the 2DA-FITC-PTXNP drug delivery system shows good stability in the PBS buffer solution for simulating the physiological environment, the drug delivery system has a good drug delivery kinetics curve in the acidic PBS buffer solution, and the half-life period t is half-life t1/2Is suitable for intravenous administration to maintain blood concentration in vivo for 8 hr.
Description
Technical Field
The invention relates to a drug-carrying system and preparation, in particular to a nanoparticle drug-carrying system and a preparation method thereof.
Background
The small molecule drugs are administrated through oral administration or injection, the drug concentration in vivo in short time far exceeds the actual demand amount, and the selectivity of entering human bodies is lacked; the metabolism is fast, the half-life period is short, the concentration in the body is reduced quickly to influence the curative effect, so that large dose administration is needed, and the side effect of the medicine is enhanced by too high medicine concentration; (2) the biomacromolecule medicine is easy to be degraded or inactivated by enzyme in vivo, has short biological half-life period and needs repeated administration; also, due to limitations of the immune system, tissues, cell membranes, etc., most of them do not easily pass through these biological barriers, and thus the bioavailability of macromolecular drugs is low. The nano drug-loading system has extremely small granularity and very large surface area, so that the drugs can be loaded in the nano carrier at high density, thereby forming local concentration and improving the utilization rate of the drugs. In addition, the nano particle carrier drug has the advantages of low toxicity, high efficiency, slow release, long acting, capability of identifying variant cells, good drug stability, no toxicity of a macromolecular carrier after the drug is released, no long-term accumulation in a body, small side effect and the like, and also has stronger directional release capability, thereby being a better substitute for various drugs.
At present, a nano particle drug-carrying system mainly takes a polymer as a main component, and the polymer has a large molecular weight, so that the nano particle drug-carrying system can be used as a drug carrier, can prolong the detention time of a drug at a focus position, and can also achieve the purpose of slow release or controllable release through diffusion or degradation of the polymer, but the nano particle drug-carrying system has the problems of difficult degradation, toxicity generation and the like.
Disclosure of Invention
The invention aims to overcome the defects of the prior art and provides an amphiphilic micromolecule self-assembly targeting nanoparticle drug delivery system and preparation thereof, so that the toxicity to normal cells is reduced, and the inhibition rate to tumor cells is improved.
The invention solves the technical problems through the following technical scheme:
an amphiphilic small molecule self-assembly targeting nanoparticle drug delivery system is characterized by comprising 2-glucosamine-fluorescent dye FITC and paclitaxel, wherein the 2-glucosamine-fluorescent dye FITC is used as a hydrophilic end of a small molecule, and the paclitaxel is used as a hydrophobic end of the small molecule.
2-glucosamine-fluorescent dye FITC is used as a 'guide group' to target tumor cells and tissues of a glucose transport receptor GLUT1 with high expression, the tumor cells and tissues are used as hydrophilic ends for forming nanoparticles, paclitaxel-glutamic acid (PTX-Glu) which is used as hydrophobic ends of the nanoparticles is covalently coupled to synthesize a 2-glucosamine and fluorochrome-paclitaxel (2DA-FITC-PTX) amphiphilic small molecular monomer with hydrophilicity and hydrophobicity, and a nano precipitation method is further used for preparing a targeting 2-glucosamine and fluorochrome-paclitaxel nanoparticle drug delivery system (2 DA-FITC-PTXNP).
The invention also provides a preparation method of the amphiphilic micromolecule self-assembly targeting nanoparticle drug delivery system, which comprises the following steps:
2.1 Synthesis of glutamic acid-paclitaxel (Glu-PTX);
2.22 preparation of glucosamine-glutamic acid-paclitaxel (2DA-NH2-Glu-PTX) prodrug;
2.32-glucosamine-fluorescent dye taxol prodrug small molecule monomer preparation;
2.42-glucosamine-fluorescent dye paclitaxel prodrug targeted nanoparticle drug delivery system preparation.
As a preferred embodiment of the present invention, 100mg (0.117mmol) of PTX was weighed out and dissolved in 15ml of Dichloromethane (DCM), while 59.7mg (0.1404mmol,1.2eqv) of Fmoc-Glu (OtBu) -OH and 14.29mg of 4-dimethylaminopyridine DMAP (0.117mmol) were added, 44.85mg (0.234mmol,2eqv) of 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (EDC) was dissolved in 10ml of DCM, 10ml of EDC solution was slowly dropped in the PTX reaction system under ice bath, after dropping for 20-30 minutes, the ice bath was removed, stirring was carried out at room temperature for 20-30 hours, and tracking was carried out by TLC. After the reaction is finished, diluting the product with DCM with the same volume, washing the product for 2 times with distilled water with the same volume, adding anhydrous magnesium sulfate, drying the product, and carrying out vacuum rotary evaporation to obtain a crystalline product, namely glutamic acid-paclitaxel.
As one of the preferred modes of the present invention, the above-mentioned glutamic acid-paclitaxel (Fmoc-Glu (OtBu) -PTX) product was dissolved in 8ml DCM and stirred overnight at room temperature until turbidity appeared and TLC tracing. And (3) performing vacuum rotary evaporation on the product again to remove the solvent, extracting the product by using diethyl ether (OtBu is dissolved in the diethyl ether), putting the product into a refrigerator for overnight, removing the diethyl ether, and drying the product to obtain Fmoc-Glu (COOH) -PTX white crystals with OtBu removed. Dissolving 0.01mmol of Fmoc-Glu (COOH) -PTX in DMF, adding EDC and NHS (molar ratio is 1:1.2:2) to activate carboxyl of Fmoc-Glu (COOH) -PTX, stirring at room temperature for 4-6 hours, adding 0.01mmol of 2DA, stirring at room temperature overnight, purifying the reaction solution by a silica gel column to obtain purified 2-amino-glutamic acid-paclitaxel (2DA-Fmoc-Glu-PTX), dissolving 2DA-Fmoc-Glu-PTX in a DCM system, adding 2ml of piperidine (making the piperidine be 20% of the total volume), extracting with diethyl ether, and tracing by TLC to obtain the 2DA-NH2-Glu-PTX prodrug.
As one of the preferable modes of the invention, after 0.1mmol2DA-NH2-Glu-PTX prodrug is added with DCM for dissolution, 0.1mmol fluorescent dye FITC is added, the mixture is stirred overnight at room temperature, the reaction solution is separated and purified by a G15 glycan gel chromatographic column, 2DA-NH2-Glu-PTX and FITC fragments which are not covalently coupled are removed, and the purified 2 glucosamine-fluorescent dye taxol prodrug (2DA-NH2-Glu-PTX-FITC) micromolecule monomer is obtained and stored at-20 ℃ for standby.
As one of the preferable modes of the invention, the nano-precipitation method is used for preparation, 0.1mmol of 2DA-NH2-Glu-PTX-FITC micromolecule monomer is dissolved in THF and transferred from an organic phase to a water phase at room temperature, the organic phase tetrahydrofuran THF is removed, and the precipitate is removed after centrifugation is carried out for 2-6min by 2500-3500 transfer, so as to obtain the uniformly distributed targeting nano drug delivery system.
Compared with the prior art, the invention has the advantages that: the 2DA-FITC-PTXNP drug delivery system can target tumor cells with GULT1 receptors highly expressed under the mediation of glucose transporter GULT1 ligand-receptors, and compared with PTX technical products, the drug delivery system can reduce the toxicity to normal cells and improve the inhibition rate to the tumor cells.
Drawings
FIG. 1 is a functional diagram of the self-contained nanoparticle drug delivery system of the present invention.
FIG. 2 is a synthesis diagram of the self-contained nanoparticle drug delivery system of the present invention.
Detailed Description
The following examples are given for the detailed implementation and specific operation of the present invention, but the scope of the present invention is not limited to the following examples.
As shown in fig. 1, an amphiphilic small molecule self-assembly targeting nanoparticle drug delivery system comprises 2-glucosamine-fluorochrome FITC and paclitaxel, wherein the 2-glucosamine-fluorochrome FITC is used as a hydrophilic end of a small molecule, and the paclitaxel is used as a hydrophobic end of the small molecule, and the targeting nanoparticle drug delivery system is self-assembled by a nano-precipitation method.
As shown in fig. 2, the preparation of the amphiphilic small molecule self-assembly targeting nanoparticle drug delivery system is characterized by comprising the following steps:
1. synthesis of glutamic acid-paclitaxel (Glu-PTX);
2.2 preparation of 2-glucosamine-glutamic acid-paclitaxel (2DA-NH 2-Glu-PTX);
3.2-glucosamine-fluorescent dye taxol prodrug micromolecule monomer is prepared;
4.2-glucosamine-fluorescent dye taxol prodrug targeted nanoparticle drug delivery system.
Examples
Preparing an amphiphilic small molecule self-assembly targeting nanoparticle drug delivery system:
1. synthesis of glutamic acid-paclitaxel (Glu-PTX)
100mg (0.117mmol) of PTX was weighed out and dissolved in 15ml of DCM, while 59.7mg (0.1404mmol,1.2eqv) of Fmoc-Glu (OtBu) -OH and 14.29mg of DMAP (0.117mmol) were added, 44.85mg (0.234mmol,2eqv) of EDC was dissolved in 10ml of DCM, 10ml of the solution in EDC was slowly dropped into the PTX reaction system under ice bath, 25 minutes of dropping was completed, the ice bath was removed, stirring was carried out at room temperature for 26 hours and tracing by TLC. After the reaction is finished, diluting the product with DCM with the same volume, washing the product for 2 times with distilled water with the same volume, adding anhydrous magnesium sulfate, drying the product, and carrying out vacuum rotary evaporation to obtain a crystalline product, namely glutamic acid-paclitaxel.
2. Preparation of glucosamine-glutamic acid-paclitaxel (2DA-NH2-Glu-PTX) prodrugs
The product glutamic acid-paclitaxel (Fmoc-Glu (OtBu) -PTX) was dissolved in 8ml DCM and stirred overnight at room temperature until turbidity appeared and TLC traced. And (3) performing vacuum rotary evaporation on the product again to remove the solvent, extracting the product by using diethyl ether (OtBu is dissolved in the diethyl ether), putting the product into a refrigerator for overnight, removing the diethyl ether, and drying the product to obtain Fmoc-Glu (COOH) -PTX white crystals with OtBu removed. Dissolving 0.01mmol of Fmoc-Glu (COOH) -PTX in DMF, adding EDC and NHS (molar ratio is 1:1.2:2) to activate carboxyl of Fmoc-Glu (COOH) -PTX, stirring at room temperature for 4-6 hours, adding 0.01mmol of 2DA, stirring at room temperature overnight, purifying the reaction solution by a silica gel column to obtain purified 2-amino-glutamic acid-paclitaxel (2DA-Fmoc-Glu-PTX), dissolving 2DA-Fmoc-Glu-PTX in a DCM system, adding 2ml of piperidine (making the piperidine be 20% of the total volume), extracting with diethyl ether, and tracing by TLC to obtain the 2DA-NH2-Glu-PTX prodrug.
Preparation of 3.2-glucosamine-fluorescent dye taxol prodrug small molecule monomer
Adding 7ml DCM into 0.1mmol2DA-NH2-Glu-PTX prodrug for dissolving, adding 0.1mmol fluorescent dye FITC, stirring overnight at room temperature, purifying the reaction solution by G15, removing the 2DA-NH2-Glu-PTX and FITC fragments which are not covalently coupled, and obtaining the purified 2-glucosamine-fluorescent dye taxol prodrug (2DA-NH2-Glu-PTX-FITC) micromolecule monomer, and storing at-20 ℃ for later use.
Preparation of 4.2-glucosamine-fluorescent dye paclitaxel prodrug targeting nanoparticle drug delivery system
The nano-precipitation method is used for preparation, 0.1mmol of 2DA-NH2-Glu-PTX-FITC micromolecule monomer is dissolved in THF and is converted into a water phase from an organic phase at room temperature, the THF of the organic phase is removed, and the precipitate is removed after 3000-rotation centrifugation for 3min, so that the uniformly distributed targeting nano-drug delivery system is obtained.
Characterization of self-contained targeted nanoparticle drug delivery systems
1. Research on drug loading capacity and drug release characteristics of autonomous targeting nanoparticle drug loading system
The drug loading capacity and the drug release characteristics of the self-contained targeting nanoparticle drug-loading system are detected by a High Performance Liquid Chromatograph (HPLC).
Respectively placing the small molecular monomer 2DA-FITC-PTX and the targeting nanoparticle drug delivery system in PBSbuffer at 37 ℃ for incubation for 100 hours, respectively taking 100uL samples at different time points (5h, 10h, 25h, 30h, 50h, 60h, 80h and 100h), sampling according to the different time points, measuring and recording the release amount of PTX by a High Performance Liquid Chromatograph (HPLC), and calculating the half-life period of release.
The theoretical paclitaxel content of the small molecule paclitaxel prodrug is 46.5% by calculation according to the molecular weight of the small molecule monomer, and the actual paclitaxel content of the nanoparticle drug-carrying system is 42.25 +/-0.16% by detection by a UV-vis method according to a standard curve equation of Y-0.77696 +0.03508X (R2-0.9999), so that the actual drug-carrying efficiency of the nanoparticle drug-carrying system is 98.8%.
2DA-FITC-PTXNP in PBS buffer at pH 7.4 simulated physiological environment, 2DA-FITC-PTXNP released slowly and continuously with release rate of 9.2% (PBS, pH 7.4) and 13% (PBS, pH 7.4+ 25%) at 25 hours in PBS buffer with or without FBS, half-life of 22 hours and 24 hours, respectively. However, in acidic PBS buffer (pH 5.5, pH 5.5+ FBS), 2DA-FITC-PTXNP had a faster release rate with 25 hour release rates of 25.2% and 27.8%, and half-lives under acidic conditions of 7.5 hours and 8 hours, respectively, indicating that acidic conditions and serum containing enzyme favour cleavage of ester bonds, thereby releasing paclitaxel drug,
2. research on in-vitro targeting of self-contained targeting nanoparticle drug delivery system
The expression levels of glucose transporter receptor (GLUT1) mRNA from normal 293T cells and from three tumor cells MDA-MB-231, MCF-7 and A549 were tested using reverse transcription PCR (RT-PCR) techniques. PBS (0.2mg/ml) water solution of a targeting nanoparticle drug-loaded system (2-DA-PTX-FITCNP) is respectively incubated in four cells (293T, MDA-MB-231, MCF-7 and A549) for 12h, the condition of the drug-loaded system entering the cells is observed under an inverted fluorescence microscope, and quantitative analysis is carried out by a flow cytometer.
The sequence of GLUT1 transport receptor mRNA expression of three tumor cells and a normal cell is as follows: MDA-MB-231> MCF-7> A549> 293T. After the 2-glucosamine-FITC-paclitaxel nanoparticle drug delivery system (2DA-FITC-PTX NP) is incubated in three tumor cells and one normal cell for 12 hours, the nanoparticle drug delivery system can be seen to enter the tumor cells under the mediation of GLUT1 transporter under an inverted fluorescence microscope, and shows stronger fluorescence intensity, while the fluorescence intensity in the normal cell 293T is weaker. The uptake rate of the prodrug in MDA-MB-231, MCF-7, A549 and 293T cells is respectively 90.19%, 80.04%, 58.12% and 6.09% by flow cytometry, and the fluorescence intensity of the three cells to be absorbed by the 2DA-FITC-PTX NP is obviously shifted, the absorption amount of the 2DA-FITC-PTX NP in MDA-MB-231 tumor cells is more than that of MCF-7, A549 and 293T, the absorption amount of the three tumor cells is far more than that of normal cells 293T, and the four cells have an order of 2DA-FITC-PTX NP uptake of MDA-MB-231> MDA-MB-435>293T, this is consistent with the sequence of the expression levels of three cell surface GLUT1 transporters, demonstrating that 2DA-FITC-PTX NP can target tumor cells mediated by the high expression of GLUT1 transporter receptors on the surface of tumor cells.
3. Research on in-vitro drug effect of autonomous targeting nanoparticle drug delivery system
Three cells MDA-MB-231, MCF-7, A549 and 293T were incubated with 2DA-FITC-PTX and 2DA-FITC-PTXNP, respectively, using the cell MTT assay. Infection was performed for 48 hours, washed 3 times with PBSpH7.0, and the medium in the wells was replaced with 180. mu.L of fresh DMEM and 20. mu.L of MTT solution (5mg/mL), and incubation was continued for 4 hours. Finally, 150 μ L of DMSO was added to each well and shaken gently at room temperature. The absorbance at 595nm of the solution in each well was measured using a microplate reader.
MTT cell experiment results show that the toxicity of the 2DA-FITC-PTXNP drug delivery system to normal cells (293T) is low, and the cell survival rate is kept above 55% even at the highest concentration. The GLUT1 receptor positive cell (MDA-MB-231) keeps low survival rate of about 20% only under the condition that the concentration is 1.625(nM), the 2DA-FITC-PTXNP drug delivery system IC50 is lower than 1/5(0.96nM) of the original drug PTX (Table1), and the experimental result shows that the 2DA-FITC-PTXNP drug delivery system has lower cytotoxicity and higher tumor cell inhibition rate compared with the 2DA-FITC-PTX and PTX original drugs. This shows that 2DA-FITC-PTXNP drug carrying system can reduce drug toxicity and improve drug effect under the mediation of GLUT1 ligand-receptor.
The above description is only for the purpose of illustrating the preferred embodiments of the present invention and is not to be construed as limiting the invention, and any modifications, equivalents and improvements made within the spirit and principle of the present invention are intended to be included within the scope of the present invention.
Claims (6)
1. An amphiphilic small molecule self-assembly targeting nanoparticle drug delivery system is characterized by comprising 2-glucosamine-fluorescent dye FITC and paclitaxel, wherein the 2-glucosamine-fluorescent dye FITC is used as a hydrophilic end of a small molecule, and the paclitaxel is used as a hydrophobic end of the small molecule; the 2-glucosamine-fluorochrome FITC is used as a 'guide group' to target tumor cells and tissues of a high-expression glucose transport receptor GLUT1, the tumor cells and the tissues are used as hydrophilic ends for forming nanoparticles, paclitaxel which is used as a hydrophobic end of the nanoparticles is covalently coupled to synthesize a 2-glucosamine fluorochrome-paclitaxel (2DA-FITC-PTX) amphiphilic small molecular monomer with hydrophilicity and hydrophobicity, and the targeting 2-glucosamine fluorochrome-paclitaxel nanoparticle drug delivery system (2DA-FITC-PTXNP) is further prepared by a nano precipitation method.
2. The method for preparing the amphiphilic small molecule self-assembly targeting nanoparticle drug delivery system of claim 1, comprising the following steps:
2.1 Synthesis of glutamic acid-paclitaxel (Fmoc-Glu (OtBu) -PTX);
2.22-glucosamine-glutamic acid-paclitaxel (2 DA-NH)2-Glu-PTX) prodrug preparation;
2.32-glucosamine-fluorochrome-paclitaxel (2DA-FITC-PTX) prodrug micromolecule monomer is prepared;
and 2.42-glucosamine-fluorochrome-paclitaxel prodrug targeted nanoparticle drug delivery system (2DA-FITC-PTXNP) preparation.
3. The preparation method of the amphiphilic small molecule self-assembly targeting nanoparticle drug delivery system of claim 2, characterized in that 100mg of PTX is dissolved in 15ml of Dichloromethane (DCM) in step 2.1, while adding 59.7mg of Fmoc-Glu (OtBu) -OH and 14.29mg of 4-dimethylaminopyridine DMAP, 44.85mg of 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (EDC) was dissolved in 10ml of DCM, under the condition of ice bath, 10ml of EDC solution is dissolved in the reaction solution and slowly dropped into the PTX reaction system, after the dropwise addition is finished for 20-30 minutes, removing the ice bath, stirring at room temperature for 20-30 hours, tracing by TLC, diluting with DCM with the same volume after the reaction is finished, then washing with distilled water of the same volume for 2 times, adding anhydrous magnesium sulfate for drying, and carrying out rotary evaporation in vacuum to obtain a crystalline product of glutamic acid-paclitaxel (Fmoc-Glu (OtBu) -PTX).
4. The method of claim 2, wherein the glutamic acid-paclitaxel (Fmoc-Glu (OtBu) -PTX) is dissolved in 8ml DCM, stirred at room temperature overnight until turbidity appears and labeled by TLC, the product is vacuum evaporated again to remove the solvent, and then extracted with ether into a refrigerator overnight, the ether is removed, the product is dried to obtain Fmoc-Glu (COOH) -PTX white crystal with OtBu removed, 0.01mmol of Fmoc-Glu (COOH) -PTX is dissolved in DMF, EDC and NHS are added to activate the carboxyl group of Fmoc-Glu (COOH) -PTX, the mixture is stirred at room temperature for 4-6 hours, 0.01mmol of 2DA is added, the mixture is stirred at room temperature overnight, the reaction solution is purified by silica gel column to obtain purified 2-amino-glutamic acid-paclitaxel (2-DA-Fmoc-Glu-PTX), dissolving 2DA-Fmoc-Glu-PTX in DCM system, adding 2ml piperidine, extracting with diethyl ether, and tracing with TLC to obtain 2DA-NH2-Glu-PTX prodrug.
5. The method for preparing the amphiphilic small-molecule self-assembly targeting nanoparticle drug delivery system according to claim 2, wherein 0.1mmol2DA-NH is added in step 2.32After DCM is added into the-Glu-PTX prodrug for dissolving, 0.1mmol of fluorescent dye FITC is added, the mixture is stirred at room temperature overnight, and the reaction solution is separated and purified by a G15 glycan gel chromatographic column to remove 2DA-NH which is not covalently coupled2-Glu-PTX and FITC fragments to give purified 2 glucosamine-fluorochrome paclitaxel prodrug (2 DA-NH)2-Glu-PTX-FITC) small molecule monomer, stored at-20 ℃ for future use.
6. The method for preparing the amphiphilic small-molecule self-assembly targeting nanoparticle drug delivery system according to claim 2, wherein the amphiphilic small-molecule self-assembly targeting nanoparticle drug delivery system is prepared by a nano-precipitation method in step 2.4, and 0.1mmol of 2DA-NH is added2Dissolving the small molecular monomer of the-Glu-PTX-FITC in THF, transferring the THF from an organic phase to a water phase at room temperature, removing the THF from the organic phase, centrifuging for 2-6min by using 2500-3500 transfer, and removing precipitates to obtain the uniformly distributed targeting nano drug delivery system.
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| US5981564A (en) * | 1998-07-01 | 1999-11-09 | Universite Laval | Water-soluble derivatives of paclitaxel, method for producing same and uses thereof |
| WO2010037395A3 (en) * | 2008-10-01 | 2010-05-20 | Dako Denmark A/S | Mhc multimers in cancer vaccines and immune monitoring |
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